Traditional approaches to reaction discovery typically focus on one particular chemical transformation. Predicted precursors for a target structure are chosen as substrates, and then particular reaction conditions are evaluated either manually or in a high-throughput format (Stambuli et al. Recent advances in the discovery of organometallic catalysts using high-throughput screening assays. Curr. Opin. Chem. Biol. 7, 420-426 (2003); Reetz,. Combinatorial and evolution-based methods in the creation of enantioselective catalysts. Angew. Chem. Int. Ed. 40, 284-310 (2001); Stambuli et al. Screening of homogeneous catalysts by fluorescence resonance energy transfer. Identification of catalysts for room-temperature Heck reactions. J. Am. Chem. Soc. 123, 2677-8 (2001); Taylor et al. Thermographic selection of effective catalysts from an encoded polymer-bound library. Science 280, 267-70 (1998); Lober et al. Palladium-catalyzed hydroamination of 1,3-dienes: a calorimetric assay and enantioselective additions. J. Am. Chem. Soc. 123, 4366-7 (2001); Evans et al. Proton-activated fluorescence as a tool for simultaneous screening of combinatorial chemical reactions. Curr. Opin. Chem. Biol. 6, 333-338 (2002); each of which is incorporated herein by reference) for their ability to produce the desired product. Although this approach is very useful in addressing specific chemical problems, it does not lend itself to the discovery of entirely new chemical reactions. In fact, its focused nature may leave many areas of chemical reactivity unexplored.
A reaction discovery system capable of simultaneously evaluating in a single solution many combinations of substrates for their ability to form new bonds and covalent structures should optimally meet the following criteria: (1) the system should organize complex substrate mixtures into discrete pairs that can react (or not react) without affecting the reactivity of the other substrate pairs; (2) the system should include a general method for separating reactive substrate pairs from unreactive pairs; and (3) the reactive substrate pairs should be easily identifiable.
Recent developments in DNA-templated synthesis suggest that DNA annealing can organize many substrates in a single solution into DNA sequence-programmed pairs. DNA-templated synthesis and in vitro selection may, therefore, be used to evaluate many combinations of substrates and conditions for bond-forming reactions (Calderone et al. Directing otherwise incompatible reactions in a single solution by using DNA-templated organic synthesis. Angew. Chem. Int. Ed. 41, 4104-8 (2002); Gartner et al. The generality of DNA-templated synthesis as a basis for evolving non-natural small molecules. J. Am. Chem. Soc. 123, 6961-3 (2001); Gartner et al. Expanding the reaction scope of DNA-templated synthesis. Angew. Chem. Int. Ed. 41, 1796-1800 (2002); Rosenbaum et al. Efficient and Sequence-Specific DNA-Templated Polymerization of Peptide Nucleic Acid Aldehydes. J. Am. Chem. Soc. 125, 13924-5 (2003); each of which is incorporated herein by reference). See also published U.S. patent application 2004/018042, published Sep. 16, 2004, which is incorporated herein by reference. Watson-Crick base pairing controls the effective molarities of substrates tethered to DNA strands. Selection for bond formation, amplification by PCR, and DNA array analysis then reveals bond-forming substrate combinations and conditions. The versatility and efficiency of DNA-templated synthesis enables the discovery of reactions between substrates typically thought to be unreactive.
Therefore, DNA-templated synthesis may be used to discover new chemical reactions that are potentially broadly useful in the synthesis of chemical compounds such as pharmaceutical agents, new materials, polymers, catalysts, etc. In the art of organic synthesis, there remains a need for additional carbon-carbon bond forming reactions. DNA-templated chemistry may be used to discover chemical reactions to satisfy this need.